Toxoplasma gondii (T. gondii) is a prevalent protozoan parasite of medical and veterinary significance. It is the etiologic agent of toxoplasmosis, a neglected disease in which incidence and symptoms differ between patients and regions. In immunocompetent patients, toxoplasmosis manifests as acute and chronic forms. Acute toxoplasmosis presents as mild or asymptomatic disease that evolves, under the host immune response, into a persistent chronic disease in healthy individuals. Chronic toxoplasmosis establishes as latent tissue cysts in the brain and skeletal muscles. In immunocompromised patients, chronic toxoplasmosis may reactivate, leading to a potentially life-threatening condition. Recently, the association between toxoplasmosis and various diseases has been shown. These span primary neuropathies, behavioral and psychiatric disorders, and different types of cancer. Currently, a direct pre-clinical or clinical molecular connotation between toxoplasmosis and most of its associated diseases remains poorly understood. In this review, we provide a comprehensive overview on Toxoplasma-induced and associated diseases with a focus on available knowledge of the molecular players dictating these associations. We will also abridge the existing therapeutic options of toxoplasmosis and highlight the current gaps to explore the implications of toxoplasmosis on its associated diseases to advance treatment modalities.

Toxoplasmosis is a prevalent disease affecting a wide range of hosts including approximately one-third of the human population. It is caused by the sporozoan parasite Toxoplasma gondii (T. gondii), which instigates a range of symptoms, manifesting as acute and chronic forms and varying from ocular to deleterious congenital or neuro-toxoplasmosis. Toxoplasmosis may cause serious health problems in fetuses, newborns, and immunocompromised patients. Recently, associations between toxoplasmosis and various neuropathies and different types of cancer were documented. In the veterinary sector, toxoplasmosis results in recurring abortions, leading to significant economic losses. Treatment of toxoplasmosis remains intricate and encompasses general antiparasitic and antibacterial drugs. The efficacy of these drugs is hindered by intolerance, side effects, and emergence of parasite resistance. Furthermore, all currently used drugs in the clinic target acute toxoplasmosis, with no or little effect on the chronic form. In this review, we will provide a comprehensive overview on the currently used and emergent drugs and their respective parasitic targets to combat toxoplasmosis. We will also abridge the repurposing of certain drugs, their targets, and highlight future druggable targets to enhance the therapeutic efficacy against toxoplasmosis, hence lessening its burden and potentially alleviating the complications of its associated diseases.

Cutaneous Leishmaniasis (CL) is a parasitic infection classified by the WHO as one of the most uncontrolled spreading neglected diseases. Syria is endemic for Leishmania tropica and Leishmania major, causing CL in the Eastern Mediterranean. The large-scale displacement of Syrian refugees exacerbated the spread of CL into neighboring countries. Therapeutic interventions against CL include local, systemic and physical treatments. The high risk for drug-resistance to current treatments stresses the need for new therapies. Imiquimod is an immunomodulatory drug with a tested efficacy against L. major species. Yet, Imiquimod efficacy against L. tropica and the molecular mechanisms dictating its potency are still underexplored. In this study, we characterized the effect of Imiquimod against L. tropica and L. major, and characterized the molecular mechanisms dictating its anti-leishmanial efficacy against both strains. We also investigated the potency and molecular mechanisms of an Imiquimod analog, EAPB0503, against these two strains. We have tested the effect of Imiquimod and EAPB0503 on macrophages infected with either L. major, L. tropica strains, or patient-derived freshly isolated L. tropica parasites. The anti-amastigote activity of either drugs was assessed by quantitative real time PCR (RT-PCR) using kinetoplast specific primers, confocal microscopy using the Glycoprotein 63 (Gp63) Leishmania amastigote antibody or by histology staining. The mechanism of action of either drugs on the canonical nuclear factor kappa- B (NF-κB) pathway was determined by western blot, and confocal microscopy. The immune production of cytokines upon treatment of infected macrophages with either drugs was assessed by ELISA. Both drugs reduced amastigote replication. EAPB0503 proved more potent, particularly on the wild type L. tropica amastigotes. Toll-Like Receptor-7 was upregulated, mainly by Imiquimod, and to a lesser extent by EAPB0503. Both drugs activated the NF-κB canonical pathway triggering an immune response and i-NOS upregulation in infected macrophages. Our findings establish Imiquimod as a strong candidate for treating L. tropica and show the higher potency of its analog EAPB0503 against CL. Cutaneous Leishmaniasis (CL) is a parasitic infection caused by Leishmania (L.) parasites. In the Old World and the Near East, CL is mainly caused by L. major and L. tropica. The ongoing Syrian war and the resulting massive population displacement led to an alarming increase in the incidence of CL, in Syria and its surrounding countries. Current therapies against CL lead to partial or complete cure in L. major infections but are less effective against L. tropica. These therapies associate with several limitations, including patients’age, immune system, repetitive painful injections, high cost, poor availability, and mainly systemic toxicity. Therefore, it is of high interest to seek for novel drugs against CL. We assessed the activity of an immunomodulatory drug and its analog against L. major and L. tropica parasites and showed their potency. Importantly, the analog proved more efficient against the wild type L. tropica strain. These results highlight the promising efficacy of immuno-modulatory drugs against CL.

The current study focused on the synthesis of doped silver nanoparticles (doped AgNPs) with yttrium (Y), gadolinium (Gd), and chromium (Cr) from pine needle leaf extract (PNLE). X-ray diffraction (XRD) was performed to assess the phase formation, detecting 61.83% from Ag and 38.17% for secondary phases of AgCl, AgO, Y, Cr-, and Gd phases. The size and shape of the NPs were determined by transmission electron microscopy (TEM), showing a spherical shape with an average particle size of 26.43 nm. X-ray photoelectron spectroscopy (XPS) detected the oxidation state of the presented elements. The scanning electron microscope (SEM) and the energy-dispersive X-ray analysis (EDX) determined the morphology and elemental composition of the NPs, respectively. Fourier transform infrared spectroscopy (FTIR) determined the different functional groups indicating the presence of Ag, Y, Gd, Cr, and other groups. Photoluminescence (PL) spectroscopy showed the optical properties of the NPs. A vibrating sample magnetometer (VSM) revealed the ferromagnetic behavior of the doped AgNPs. The antibacterial activity of the doped AgNPs was tested against six uro-pathogenic bacteria (Staphylococcus aureus, Staphylococcus haemolyticus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa) using the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) microdilution assays, agar well diffusion assay, time–kill test, and antibiofilm screening assays, revealing significant activity, with MICs ranging between 0.0625 and 0.5 mg/mL and antibiofilm activity between 40 and 85%. The antioxidant activity was determined by the 1,1, diphenyl 1-2 picrylhydrazyl (DPPH) radical scavenging assay with a potential of 61.3%. The docking studies showed that the doped AgNPs had the potential to predict the inhibition of crucial enzymes such as penicillin-binding proteins, LasR-binding proteins, carbapenemase, DNA gyrase, and dihydropteroate synthase. The results suggest that the doped AgNPs can be applied in different medical domains.

To treat urinary tract infections (UTIs), biosynthesized silver and yttrium‐doped silver nanoparticles (AgNPs and Y‐AgNPs) were synthesized from pine needle leaf extract (PNLE). The crystalline nature of the NPs was demonstrated by X‐ray diffraction. Transmission and scanning electron microscopy showed that AgNPs and Y‐AgNPs are dispersed and spherical, with average particle sizes of 18.43 and 26.58 nm, respectively. The chemical composition and oxidation states were revealed by X‐ray photoelectron spectroscopy, while the elemental compositions were explored by energy‐dispersive X‐ray analysis. The functional groups and absorbance peaks were revealed by Fourier transform infrared spectroscopy and ultraviolet‐visible spectroscopy, respectively. The NPs possessed luminescent behavior based on photoluminescence studies and ferromagnetic behavior according to vibrating sample magnetometer analysis. In addition, antibacterial activity against six uropathogenic bacteria was assessed by performing microdilution assays to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) which ranged between 0.0625 and 2 mg/mL, agar well diffusion assay with zones of inhibition 8–17 mm, time‐kill test detecting inhibition after 3 h, and antibiofilm screening assays at concentrations ranging between 0.0625 and 1 mg/mL. The antioxidant activity was determined by the 1,1, diphenyl 1‐2 picrylhydrazyl (DPPH) radical scavenging assay, which showed a significant antioxidant activity (14.2%–55.6%). Docking studies showed that AgNPs and Y‐AgNPs can inhibit the vital enzymes DNA gyrase, penicillin‐binding proteins, carbapenemase, LasR‐binding protein, and dihydropteroate synthase. These results highlight the use of AgNPs and Y‐AgNPs as alternative approaches in the battle against antibiotic‐resistant UTIs. The research illustrates the increased bioactivity of Y‐AgNPs compared with conventional AgNPs. It paves the way for the use of novel nanomaterials in antimicrobial medicine.